Endoplasmic Reticulum and Mitochondrial Stresses and Their Crosstalk in Neurodegenerative Diseases and Stroke

Persistent endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR) through IRE1α, PERK, and ATF6 pathways. While initially protective, chronic UPR signaling disrupts mitochondrial function via mtROS generation, caspase-2 activation, and impaired mitochondria-associated membranes (MAMs). These disruptions compromise mitochondrial integrity, elevate oxidative stress, and critically contribute to neuronal dysfunction in a range of severe neurological conditions, including the acute injury phase and subsequent progression of stroke, alongside neurodegenerative diseases such as Parkinson’s, Alzheimer’s, Huntington’s, and ALS.Adaptive UPR mechanisms which aim to restore proteostasis, can turn maladaptive, by promoting apoptosis (via CHOP, caspase-12) and dysregulating ER–mitochondria calcium signaling, for example. This results in mitochondrial calcium overload, membrane depolarization, ATP depletion, and increased ROS, leading to impaired mitophagy and even more severe mitochondrial dysfunction. This creates a vicious cycle where ER and mitochondrial stresses amplify each other, fueling progressive neuronal death and exacerbating injury in acute events like ischemia-reperfusion following stroke.Moreover, stressed mitochondria release mtDNA, ROS, and DAMPs, activating the NLRP3 inflammasome and IL‑1β-driven neuroinflammation. In glial cells, ER stress and UPR-related signaling sway microglia and astrocytes toward pro-inflammatory phenotypes, worsening neuroinflammation and further compromising mitochondrial quality control. These pathological interactions underlie, and accelerate, a broad spectrum of neurological conditions, encompassing neurodegenerative diseases, acute brain injuries like stroke, and even certain psychiatric conditions, all characterized by disrupted proteostasis and energy failure.This Research Topic seeks to clarify molecular mechanisms linking ER and mitochondrial stress in neurodegeneration and stroke, and to highlight future therapeutic approaches targeting these inter-organelle interactions. Potential sub-themes may include, but are not limited to:• UPR signaling pathways (PERK, IRE1α, ATF6) and their impact on mitochondria• Mitochondria-associated membrane (MAM) dynamics in neurodegeneration and stroke pathology• Mitochondrial dysfunction, oxidative stress, and impaired mitophagy• Feedback loops between ER and mitochondrial stress• Neuroinflammatory signaling: NLRP3 inflammasome and glial activation• Disruption of proteostasis and bioenergetic failure in disease progression and acute neurological injury• Multi-target therapeutic strategies to restore ER-mitochondrial homeostasis Topic editors: Sandeep Kumar, Catherine (Chi) Weindel, Ayan Mohamud Yusuf, Dirk M. Hermann Source: https://www.frontiersin.org/research-topics/74556/endoplasmic-reticulum-and-mitochondrial-stresses-and-their-crosstalk-in-neurodegenerative-diseases-and-stroke